Vaginal microbicides provide the best opportunity to develop a practical method for preventing sexual transmission of HIV. Spermicides containing nonoxynol-9 may prevent HIV transmission but the tissue irritation produced by these products may abrogate any beneficial effects. N-docosanol is a saturated alcohol which inhibits the replication of enveloped viruses in -vitro. The potential of this compound as a topical microbicide to prevent HIV transmission was tested in the SIV/rhesus macaque system. Six mature female rhesus macaques were treated by placing 12.5% N-docosanol cream into the vagina before vaginal challenge with sivmac251. Prior to SIV challenge each animal was treated twice with the n-docosanol cream (1 hour and 5 minutes prior to SIV challenge) and care was taken to insure that the cream completely covered the cervicovaginal mucosa. The animals were then challenged with 1 ml of sivmac251 (102 tcid50) mixed with 0.25 Ml human seminal plasma. One hour after SIV challenge, a third application of 1 ml n-docosanol was placed in the vagina of the animals. Two naive control animals were challenged vaginally with the same virus inoculum. Both naive control animals became persistently viremic and seroconverted to SIV antigens (this dose of SIV has been used previously to infect 7 of 7 female rhesus macaques). One n-docosanol treated animal became persistently SIV-infected and seropositive. The remaining 5 n-docosanol treated animals remain uninfected and seronegative. These results demonstrate that n-docosanol cream is capable of preventing the vaginal transmission of SIV and suggest that a preparation containing this compound may be useful in preventing sexual transmission of HIV.